Although MRI-based techniques have provided insights into the function of brain regions involved in migraine, there is little understanding of he molecular mechanisms affected during the course of this disorder. Understanding this process in vivo is crucial to determine the systems involved in the persistence and relief of migraine, especially the ?-opioidergic system, arguably one of the principal endogenous pain modulatory systems in the brain. Recent studies from our lab using positron emission tomography (PET) with a selective radiotracer for ?-opioid receptor (?OR), [11C]carfentanil, have demonstrated that there is a decrease in ?OR availability (non-displaceable binding potential - ?OR BPND) in the thalamus, and other pain-related regions, in the brains of migraineurs during the headache (ictal) and non-headache (interictal) phases. The thalamus is the major relay structure in the forebrain for (non)-noxious inputs, which will be distributed subsequently to multiple cortical areas for discriminative, cognitive and affective processing. Unfortunately, exogenous opioids are unable to selectively target those dysfunctional brain regions without inducing multiple adverse effects and functional impairments. In fact, prolonged opioid therapy has been associated with migraine endurance and worsening. Interestingly, our recent studies have also shown that modulation of such ?-opioid mechanisms can be accurately achieved using a noninvasive tool, namely transcranial direct current stimulation (tDCS), and that it can produce analgesic after-effects in chronic migraine and other trigeminal pain disorders. However, the electric fields generated by its most conventional analgesic montage are widely spread across the brain, lacking specificity on the pain-related structures directly targeted. Recently, a novel high-definition tDCS (HD- tDCS) montage (Villamar et al., 2013) created by our group based on epidural M1 stimulation principles reduced exclusively contralateral sensory-discriminative clinical pain measures (pain intensity/area) in chronic trigeminal pain patients. Therefore, the main goals of our study are: First, to exploit the ?-opioidergic dysfunction in vivo in migraine patients and allodynia compared to healthy controls; second, to determine whether 10 daily sessions of non-invasive and precise M1 HD-tDCS have a modulatory effect on clinical and experimental pain measures in episodic migraine patients; and third, to investigate whether repetitive active M1 HD-tDCS induces/reverts ?OR BPND changes in the thalamus and other pain-related regions, and whether those changes are correlated with migraine pain measures. The studies above represent a change in paradigm in migraine research, as we directly investigate and modulate in vivo one of the most important endogenous analgesic mechanisms in the brain.